Tri-(adamantyl)phosphines and applications thereof

ABSTRACT

In one aspect, phosphine compounds comprising three adamantyl moieties (PAd3) and associated synthetic routes are described herein. Each adamantyl moiety may be the same or different. For example, each adamantyl moiety (Ad) attached to the phosphorus atom can be independently selected from the group consisting of adamantane, diamantane, triamantane and derivatives thereof. Transition metal complexes comprising PAd3 ligands are also provided for catalytic synthesis including catalytic cross-coupling reactions.

RELATED APPLICATION DATA

The present application is a divisional application pursuant to 35U.S.C. § 120 of U.S. patent application Ser. No. 15/770,709 filed Apr.24, 2018, which is a U.S. National Phase of PCT/US2016/059698 filed Oct.31, 2016, which claims priority pursuant to 35 U.S.C. § 119(e) to U.S.Provisional patent Application Ser. No. 62/248,056 filed Oct. 29, 2015,each of which is hereby incorporated by reference in its entirety.

FIELD

The present invention relates to phosphine compounds comprising threeadamantyl moieties (PAd₃) and, in particular, to transition metalcomplexes incorporating PAd₃ ligand for cross-coupling catalysis.

BACKGROUND

Modern synthetic organic methods utilizing homogeneous transition metalcatalysis have benefited immensely from the capacity of phosphines tomodify the activity, selectivity and stability of metal catalysts. As acorollary, the behavior of metal catalysts can be manipulated by tuningthe steric and electronic properties of supporting ligands such asphosphines. Thus, the discovery of novel phosphine structures withsteric and/or electronic properties beyond what can be accessed usingexisting phosphorus-based ancillary ligands is desirable. Newerapplications of phosphines to organocatalysis, frustrated Lewis pair(FLP) catalysis, biorthogonal reactions, and nano-materials should alsobenefit from access to new phosphine properties.

SUMMARY

In one aspect, phosphine compounds comprising three adamantyl moieties(PAd₃) and associated synthetic routes are described herein. Eachadamantyl moiety may be the same or different. For example, eachadamantyl moiety (Ad) attached to the phosphorus atom can beindependently selected from the group consisting of adamantane,diamantane, triamantane and derivatives thereof. Therefore, a series ofPAd₃ compounds are contemplated. In another aspect, a method ofsynthesizing a PAd₃ compound comprises providing a reaction mixtureincluding di-(adamantyl)phosphine (PAd₂) and a substituted adamantylmoiety and reacting the PAd₂ and substituted adamantyl moiety via anS_(N)1 pathway to provide PAd₃. In other embodiments, a method ofsynthesizing a PAd₃ compound comprises providing a reaction mixtureincluding di-(adamantyl)phosphide and a substituted adamantyl moiety andreacting the di-(adamantyl)phosphide and substituted adamantyl moietyvia an S_(N)1 pathway to provide PAd₃.

In another aspect, metal complexes are provided. A metal complexcomprises at least one transition metal and one or more PAd₃ ligandsdescribed herein coordinated to the transition metal. In someembodiments, a metal complex is of the formula (PAd₃)_(m)M(L)_(n)wherein M is the transition metal, L is ligand and m and n are eachintegers from 1 to 3.

In a further aspect, methods of catalysis are described herein,including catalytic cross-coupling reactions. A method ofcross-coupling, in some embodiments, comprises providing a reactionmixture including a substrate, a coupling partner and a transition metalcomplex comprising PAd₃ ligand and reacting the substrate and couplingpartner in the presence of the transition metal complex or derivativethereof to provide cross-coupled reaction product. In some embodiments,the substrate can be selected from substituted aromatic compounds orsubstituted unsaturated aliphatic compounds. Moreover, the couplingpartner can comprise a variety of species including, but not limited to,organoboron compounds, organolithium compounds, organozinc compounds,organosilicon compounds, Grignard reagents and/or compounds havinglabile C—H bonds.

These and other embodiments are further described in the detaileddescription which follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1(a) illustrates various PAd₃ compounds according to someembodiments.

FIG. 1(b) illustrates various salt forms of the PAd₃ compounds of FIG.1(a) according to some embodiments.

FIG. 2 illustrates synthesis of one embodiment of a PAd₃ compounddescribed herein.

FIG. 3 illustrates several transition metal complexes incorporating PAd₃ligands according to some embodiments.

FIG. 4 illustrates several transition metal complexes incorporating PAd₃ligands according to some embodiments.

FIG. 5(a) illustrates various phenol leaving groups of aryl substratesaccording to some embodiments.

FIG. 5(b) illustrates various thiophenol leaving groups of arylsubstrates according to some embodiments.

FIG. 6 illustrates Suzuki-Miyaura coupling with transition metal complexdescribed herein according to some embodiments.

FIG. 7 illustrates coupling partner compounds (R′—H) having reactive C—Hbonds according to some embodiments.

FIG. 8 illustrates Suzuki-Miyaura polymerization with transition metalcomplex described herein according to some embodiments.

FIG. 9 illustrates Kumada-Tamao-Corriu coupling with transition metalcomplex described herein according to some embodiments.

FIG. 10 illustrates Buchwald-Hartwig amination with transition metalcomplex described herein according to some embodiments.

FIG. 11 illustrates α-arylation with transition metal complex describedherein according to some embodiments.

FIG. 12 illustrates cross-coupling with transition metal complexdescribed herein according to some embodiments.

FIG. 13 illustrates one embodiment of a transition metal catalystdescribed herein.

DETAILED DESCRIPTION

Embodiments described herein can be understood more readily by referenceto the following detailed description and examples and their previousand following descriptions. Elements, apparatus and methods describedherein, however, are not limited to the specific embodiments presentedin the detailed description and examples. It should be recognized thatthese embodiments are merely illustrative of the principles of thepresent invention. Numerous modifications and adaptations will bereadily apparent to those of skill in the art without departing from thespirit and scope of the invention.

Definitions

The term “alkyl” as used herein, alone or in combination, refers to astraight or branched saturated hydrocarbon group optionally substitutedwith one or more substituents. For example, an alkyl can be C₁-C₃₀.

The term “alkenyl” as used herein, alone or in combination, refers to astraight or branched chain hydrocarbon group having at least onecarbon-carbon double bond.

The term “aryl” or “arene” as used herein, alone or in combination,refers to an aromatic monocyclic or multicyclic ring system optionallysubstituted with one or more ring substituents

The term “heteroaryl” or “heteroarene” as used herein, alone or incombination, refers to an aromatic monocyclic or multicyclic ring systemin which one or more of the ring atoms is an element other than carbon,such as nitrogen, oxygen and/or sulfur.

The term “alkoxy” as used herein, alone or in combination, refers to themoiety RO—, where R is alkyl, alkenyl or aryl defined above.

The term “fluoroalkyl” as used herein refers to an alkyl group definedabove wherein one or more hydrogen atoms are replaced by fluorine atoms.

I. PAd₃ Compounds

In one aspect, phosphine compounds comprising three adamantyl moieties(PAd₃) and associated synthetic routes are described herein. Eachadamantyl moiety may be the same or different. For example, eachadamantyl moiety (Ad) attached to the phosphorus atom can beindependently selected from the group consisting of adamantane,diamantane, triamantane and derivatives thereof. In some embodiments,for example, all the adamantyl moieties (Ad) may be the same. In otherembodiments, all adamantyl moieties (Ad) may be different. In furtherembodiments, two adamantyl moieties (Ad) may be the same while the thirdadamantyl moiety (Ad) is different. Accordingly, use of the commonabbreviation Ad for adamantyl moieties of PAd₃ compounds is not to beconstrued as imparting any structural similarity or difference betweenthe three adamantyl moieties.

FIG. 1(a) illustrates various PAd₃ compounds according to someembodiments described herein. As illustrated in FIG. 1 , R¹, R² and R³can be independently selected from several adamantyl moieties (Ad) toprovide a series of PAd₃ compounds of differing structure. In someembodiments, adamantyl moieties (Ad) of PAd₃ compounds are substitutedat one or more positions. Adamantyl moieties, for example, can includeone or more acyl-, aryl-, alkyl-, alkoxy-, alkyl-amine and/or alcoholsubstituents. PAd₃ compounds can also exist in salt form as illustratedin FIG. 1(b).

Synthetic routes for PAd₃ compounds are also described herein. In oneaspect, a method of synthesizing a PAd₃ compound comprises providing areaction mixture including di-(adamantyl)phosphine (PAd₂) and asubstituted adamantyl moiety and reacting the PAd₂ and substitutedadamantyl moiety via an S_(N)1 pathway to provide PAd₃. Adamantylmoieties of PAd₂ can be independently selected from adamantane,diamantane, triamantane and derivatives thereof. Similarly, thesubstituted adamantyl moiety can have an adamantane, diamantane ortriamantane architecture. In one non-limiting embodiment, the PAd₃compound illustrated in structure of formula (I) below is synthesizedaccording to the foregoing method.

A reaction mixture including di-1-adamantylphosphine and a substitutedadamantane is provided. The di-1-adamantylphosphine and substitutedadamantane are reacted via an S_(N)1 pathway to providetri(1-adamantyl)phosphine. The substituted adamantane, in someembodiments, is of formula (II)

wherein X is a moiety operable for dissociation into an anion under theS_(N)1 pathway. In some embodiments, for example, X is selected from thegroup consisting of acetate, triflate, tosylate and hydroxyl. FIG. 2provides specific reaction conditions of the S_(N)1 route for synthesisof the PAd₃ compound of formula (I) according to one embodiment.Diamantane and triamantane moieties can also be functionalized with aleaving group to provide substituted adamantane for reaction with PAd₂via an S_(N)1 pathway. The leaving group of these higher adamantanestructures can also be selected from the group consisting of acetate,triflate, tosylate and hydroxyl.

In other embodiments, a method of synthesizing PAd₃ compounds describedherein comprises providing a reaction mixture includingdi-(adamantyl)phosphide and a substituted adamantyl moiety and reactingthe di-(adamantyl)phosphide and substituted adamantyl moiety via anS_(N)1 pathway to provide PAd₃. Suitable substituted adamantyl moietycan include a leaving group, X, as described above. Moreover, suitablecounterions of the phosphide, in some embodiments, are cations of basesused to deprotonate PAd₂ and can include alkali ions, MgCl⁺ and ZnBr⁺.Moreover, strong amine bases for which the pKa (H₂O) of the amineconjugate acid exceeds approximately 10 may be employed as counterions.Such species can include tertiary ammonium ions

It is particularly noted that PAd₃ compounds of the present disclosureexhibit significant kinetic stability toward oxidation, therebypermitting storage under air with negligible oxidation. Additionally,synthetic methods described herein can provide PAd₃ compounds at yieldsexceeding 50 percent or 60 percent.

II. Metal Complexes

In another aspect, metal complexes are provided. A metal complexcomprises at least one transition metal and one or more PAd₃ compoundsdescribed in Section I above as ligand coordinated to the transitionmetal. Any transition metal operable to coordinate with phosphineligands can be used to provide a metal complex described herein. In someembodiments, the transition metal is selected from Group VIIIA, IB orIIB of the Periodic Table. Groups of the Periodic Table described hereinare identified according to the CAS designation. Further, the transitionmetal can be a noble metal including, but not limited to, palladium,rhodium, silver and gold. In some embodiments, the metal complexcomprises two transition metals, wherein PAd₃ ligands are coordinated toone or each of the transition metals. Non-PAd₃ ligands bridging thetransition metal centers can include halo, η³-allyl, η³-crotyl,η³-cinnamyl and η³-indenyl.

Moreover, the metal complex can be of the formula (PAd₃)_(m)M(L)_(n)wherein M is the transition metal, L is ligand and m and n are eachintegers from 1 to 3. L can generally comprise any species meeting thesteric requirements set by the PAd₃ ligand(s). In some embodiments, forexample, L can be selected from the group consisting of alkyl, aryl,halo, CO, cyano, hydroxyl, acetate, substituted benzoate,trifluoroacetate (TFA), tosylate (OTs), mesylate (OMs), triflate (OTf),η³-allyl, η³-crotyl, η³-cinnamyl and η³-indenyl. In embodiments whereinn is greater than 1, the chemical identity of L ligands can be the sameor different. FIGS. 3 and 4 illustrate non-limiting examples of metalcomplexes employing PAd₃ ligands described herein. The adamantylmoieties (Ad) of the metal complexes illustrated in FIGS. 3 and 4 areadamantane. It is contemplated that any combination of adamantane,diamantane and/or triamantane moieties can be present in PAd₃ ligands ofthe metal complexes.

III. Catalytic Cross-Coupling

In a further aspect, methods of catalysis are described herein,including catalytic cross-coupling reactions. A method ofcross-coupling, in some embodiments, comprises providing a reactionmixture including a substrate, a coupling partner and a transition metalcomplex comprising PAd₃ ligand and reacting the substrate and couplingpartner in the presence of the transition metal complex or derivativethereof to provide cross-coupled reaction product. The transition metalcomplex can have any composition and/or properties described in SectionII hereinabove.

The substrate can generally be selected from substituted aromaticcompounds or substituted unsaturated aliphatic compounds. Suitablesubstituted aromatic compounds can include monocyclic and multicyclicring systems, such as fused and non-fused multicyclic ring systems.Substituted aryl compounds can also comprise heteroaryl species,including monocyclic and multicyclic heteroaryl systems. Multicyclicheteroaryl systems can comprise fused and non-fused ring structures suchas fused or non-fused heteroaryl rings as well as heteroaryl rings fusedor non-fused to aryl rings. A substituted aromatic compound of thereaction mixture comprises a leaving group. Any leaving group operableto undergo cross-coupling mechanistic pathways described herein can beemployed. A leaving group, in some embodiments, is selected from thegroup consisting of halo, tosylate (OTs), mesylate (OMs), nosylate(ONs), N₂ ⁺X⁻, N₂NR¹R² and NMe₃ ⁺, wherein X⁻ is halide and R¹ and R²are alkyl. In additional embodiments, a leaving group can be based onphenol derivatives of the aromatic compound including, but not limitedto, carbamates, phosphonates, carbonates, sulfates, carboxylates andsulfamates. FIG. 5(a) illustrates various phenol derivative leavinggroups according to some embodiments. R¹ and R² in the embodiments ofFIG. 5(a) can be alkyl or other suitable aliphatic or substitutedaliphatic group. FIG. 5(b) illustrates thiophenol derivative leavinggroups, wherein R can be alkyl or other suitable aliphatic orsubstituted aliphatic group.

Aromatic substrates can also comprise one or more ring substituents inaddition to the leaving group. As illustrated in the non-limitingembodiments of FIG. 6 and the examples below, aromatic substrates cancomprise one or more ring substituents selected from the groupconsisting of alkyl, cycloalkyl, alkoxy, acyl, nitro, nitrile, hydroxyland amide.

Substrates of cross-coupling reactions described herein also includesubstituted unsaturated aliphatic compounds. Substituted unsaturatedaliphatic compounds can exhibit a single point of unsaturation, such asin vinyl or allyl compounds. In other embodiments, substitutedunsaturated aliphatic compounds can have more than one point ofunsaturation. As with aromatic substrates, substituted aliphaticcompounds comprise a leaving group. For example, a substitutedunsaturated aliphatic compound can comprise any of the leaving groupsdescribed above for substituted aromatic compounds. In some embodiments,a leaving group is attached to allyl or vinyl moieties to providesubstituted unsaturated aliphatic substrate. In such embodiments, thevinyl or allyl group can include one or more substituents in addition tothe leaving group, including alkyl and/or acyl substituents.

The coupling partner of the reaction mixture can comprise a variety ofspecies including, but not limited to, organoboron compounds,organolithium compounds, organozinc compounds, organosilicon compoundsand Grignard reagents. Organic moieties of these organometalliccompounds can comprise aromatic moieties and aliphatic moieties.Suitable aryl moieties can include monocyclic and multicyclic ringsystems, such as fused and non-fused multicyclic ring systems. Arylmoieties can also comprise heteroaryl species, including monocyclic andmulticyclic heteroaryl systems. Multicyclic heteroaryl systems cancomprise fused and non-fused ring structures such as fused or non-fusedheteroaryl rings as well as heteroaryl rings fused or non-fused to arylrings. In some embodiments, aromatic moieties comprise one or more ringsubstituents selected from the group consisting of alkyl, cycloalkyl,fluoroalkyl and halo.

Suitable aliphatic moieties of organometallic coupling partners includeunsaturated moieties, such as vinyl or allyl groups, as well assaturated moieties. In some embodiments, for example, an unsaturatedcarbon is coupled to the metal or metalloid of the organometalliccompound. In other embodiments, a branch point carbon of a saturatedaliphatic moiety is coupled to the metal or metalloid of theorganometallic compound. Alternatively, a non-branch point carbon of asaturated aliphatic moiety can be coupled to the metal or metalloid ofthe organometallic compound.

In further embodiments, a coupling partner comprises a compound having alabile C—H bond. Compounds having reactive C—H bonds, in someembodiments, comprise amines, phosphines, phosphonates, aliphaticcarboxylic acids and esters, aliphatic dicarboxylic acids and esters,ketones, nitriles, nitroalkanes, unsaturated aliphatic compounds andaromatic compounds, including aryl and heteroaryl compounds.Heteroarenes can be especially reactive when one or two electronegativeatoms are adjacent to the labile C—H bond. FIG. 7 illustrates variousnon-limiting embodiments of coupling partner compounds comprisingreactive C—H bonds.

When employing organoboron coupling partner, cross-coupling reactionsdescribed herein can proceed via Suzuki-Miyaura coupling orSuzuki-Miyaura polycondensation. FIG. 6 illustrates a number ofSuzuki-Miyaura couplings employing transition metal complex describedherein as catalyst. The cross-couplings illustrated in FIG. 6 arediscussed in further detail in the examples below. Table I listsadditional catalytic schemes and associated figures employing transitionmetal catalyst described herein.

TABLE I Cross Coupling Reactions Coupling Partner Catalytic SchemeExample

Suzuki-Miyaura polymerization FIG. 8 Grignard ReagentKumada-Tamao-Corriu FIG. 9 (R—Mg—X) coupling Alkyl amine/aryl amineBuchwald-Hartwig amination FIG. 10 Carbonyl species-ketone, α-arylationFIG. 11 ester, amide, imideTransition metal complex can be present in the reaction mixture in anyamount not inconsistent with objectives of the present invention.Generally, transition metal complex can be present in an amount of0.005-5 mol %. Transition metal complex can also be present in thereaction mixture in an amount selected from Table II.

TABLE II Transition Metal Complex Loading (mol. %) 0.01-3  0.01-1 0.01-0.5  0.01-0.25 0.01-0.1 ≤0.5 ≤0.1In some embodiments, transition metal complex described herein is formedprior to addition to the reaction mixture. Alternatively, PAd₃ ligandand transition metal complex precursor are added to the reaction mixturefor in-situ formation of the catalytic transition metal complex orderivative thereof. FIGS. 9 and 12 , for example, illustrate addition ofPAd₃ ligand and transition metal complex precursor to the reactionmixture for catalytic cross-coupling of substrate and coupling partner.

Cross-coupling methods described herein can exhibit product yieldsgreater than 50 percent. In some embodiments, product yield ranges from60-99 percent. Cross-coupling methods described herein can also exhibitproduct yields selected from Table III.

TABLE III Product Yield (%) 70-99 75-99 80-99 90-99 95-99 >90Further, transition metal complex described herein can exhibit highturnover numbers (TON) and high turnover frequencies (TOF). For example,transition metal complex, in some embodiments, displays TON of at least1.5×10⁴ and TOF of at least 1×10⁵ h⁻¹.

These and other embodiments are further illustrates by the followingnon-limiting examples.

General Methods

All reactions were conducted inside a dry nitrogen filled glove box orusing standard Schlenk techniques unless otherwise noted. Solvents werepurchased from Aldrich or Fisher and purified in a solvent purificationsystem by percolation through neutral alumina under positive pressure ofnitrogen. All chemical reagents were used as received from Aldrich,Combi-Blocks, and TCI unless otherwise noted. Tribasic potassiumphosphate granular powder purchased from Fisher was nominally determinedto be ca. K₃PO₄.5H₂O according to mass loss measurement after drying at65° C. for 10 h in a vacuum oven, though this is likely an admixture ofthe known hydrates K₃PO₄.3H₂O and K₃PO₄.7H₂O. Tribasic potassiumphosphate monohydrate was purchased from Aldrich and ground with amortar and pestle prior to use. Potassium hydroxide was purchased fromEMD Millipore and ground with a mortar and pestle prior to use.Bis-{2-[(acetyl-κO)amino]phenyl-κC}bis[μ(p-toluenesulfonate)]dipalladiumwas prepared according to literature procedure.

All products are purified with forced-flow chromatography on TeledyneIscoRediSep® prepacked silica gel columns. Infrared spectra (FT-IR) wereobtained in dichloromethane solution on a Thermo Nicolet spectrometerfor Rh(acac)(CO)(L) complexes. ¹H, ¹³C {¹H}, ³¹P{¹H} nuclear magneticresonance spectra (NMR) were obtained on a Bruker 300 MHz or 500 MHzspectrometer and values reported in ppm (δ) referenced against residualCHCl₃, CHDCl₂, etc. Spin-spin coupling constants are described assinglet (s), doublet (d), triplet (t), quartet (q), quintet (quint),broad (br) or multiplet (m), with coupling constants (J) in Hz. Highresolution mass spectrometry (HR-MS) data were obtained using an Agilent6210 High Resolution Electrospray TOF-MS.

Example 1—Preparation of tri(1-adamantyl)phosphine

An oven-dried 100 ml round-bottomed flask equipped with a magnetic stirbar was charged with di-1-adamantylphosphine (2.35 g, 7.77 mmol, 1.0equiv) and 1-adamantylacetate (1.66 g, 8.54 mmol, 1.1 equiv) in theglove box. dichloromethane (40 ml) was added to dissolve the entiresolid. The flask was capped with a rubber septum, and taken out of theglove box. Me₃SiOTf (1.69 ml, 9.32 mmol, 1.2 equiv) was added by syringeand the reaction mixture was stirred at room temperature for 24 h.Triethylamine (5.4 ml, 39 mmol, 5.0 equiv) was then added and thereaction was stirred for an additional 0.5 h at room temperature. Theneutralized PAd₃ subsequently precipitated from solution and wasisolated by simple filtration on a disposable filter funnel followed byrinsing with ethanol (50 ml). After aspiration for 0.5 h, 2.2 g (63%) of1 obtained as a pure white powder. Although a solution of PAd₃ is proneto oxidation under air, material in the solid state can be stored on thebench top for at least three months without substantial decomposition.Note that slow decompose in chlorinated solvent (dichloromethane,chloroform) was observed even under an inert atmosphere, but thecompound appears stable in solutions of THF, benzene and toluene underNa.

¹H NMR (501 MHz, CD₂Cl₂) δ 2.13 (br, 18H), 1.84 (br, 9H), 1.74-1.58 (m,18H).

¹³C NMR (126 MHz, CD₂Cl₂) δ 42.68 (br), 41.10 (d, J=34.3 Hz), 37.0, 29.5(d, J=7.2 Hz).

³¹P NMR (121 MHz, C₆D₆) δ 59.35.

HRMS (ESI) m/z calculated for C₃₀H₄₆PO (M+17) 453.3286, found 453.3289.

Example 2—Preparation of Rh(acac)(CO)(PAd₃)

PAd₃ (22 mg, 50 μmmol, 1 equiv) and Rh(acac)(CO)₂ (12.9 mg, 50 μmmol, 1equiv) were dissolved in THF (2 mL) inside the glove box and stirred for12 h. After evaporation of solvent and purification of the residue byflash chromatography (90% hexane, 10% ethyl acetate) and drying of theresulting solid under vacuum, 10.5 mg (32%) of the metal complex wasobtained as yellow powder.

¹H NMR (300 MHz, CDCl₃) δ 5.52 (s, 1H), 2.62 (br, 18H), 2.08 (s, 3H),2.08-1.98 (br, 9H), 1.94 (s, 3H), 1.90-1.62 (m, 18H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 192.9 (dd, J=76.8, 19.3 Hz), 188.1,184.0, 100.9 (d, J=2.5 Hz), 48.2 (d, J=7.3 Hz), 42.3 (br), 36.8 (br),29.6 (d, J=7.6 Hz), 27.7 (d, J=4.6 Hz), 27.1.

³¹P{¹H} NMR (121 MHz, CDCl₃) δ 90.6 (d, J=174.6 Hz).

Example 3—Preparation of Catalyst{2-[(acetyl-κO)amino)phenyl-κC](tri-1-adamantylphosphine)palladium}⁺(p-toluenesulfonate)⁻

Tri(1-adamantyl)phosphine (44 mg, 0.1 mmol, 1 equiv) andbis-{2-[(acetyl-KO)amino]phenyl-κC}bis[μ-(4-methylbenzenesulfonate)]dipalladium(41 mg, 0.05 mmol, 0.5 equiv) were weighed into a 20 ml scintillationvial with a magnetic stir bar and brought into glove box. THF (4 ml) wasadded to the solid. The reaction mixture was stirred at room temperaturefor 20 min, then concentrated to ca. 1 ml and diluted with diethyl ether(15 ml). The resulting solid that formed was isolated by filtration thendried under vacuum to afford 75 mg (88%) of catalyst as a yellow powder.Catalyst structure is illustrated in FIG. 13 . Crystals suitable forsingle crystal X-ray diffraction were grown from a THF solution at roomtemperature.

¹H NMR (501 MHz, CD₂Cl₂) δ 12.32 (s, 1H), 7.80 (d, J=7.8 Hz, 2H),7.52-7.41 (m, 2H), 2.35-2.31 (m, 1H), 7.18 (m, 3H), 6.89-6.82 (m, 1H),2.49 (s, 3H), 2.45 (br, 18H), 2.40 (s, 3H), 2.11 (br, 9H), 1.84 (br,18H).

³¹P NMR (203 MHz, CD₂Cl₂) δ 47.24.

¹³C NMR (126 MHz, CD₂Cl₂) δ 169.73 (d, J=2.3 Hz), 144.09, 142.19 (d,J=10.0 Hz), 139.32, 132.65 (d, J=1.6 Hz), 128.53, 127.43, 125.84, 123.40(d, J=5.6 Hz), 120.77, 117.77 (d, J=6.6 Hz), 48.36 (d, J=6.2 Hz), 41.56,36.08, 29.04 (d, J=7.7 Hz), 21.04 (d, J=3.5 Hz), 20.99.

Example 4—Preparation of Pd(PAd₃)(Ph)(κ²-OAc)

Pd(py)₂(Ph)(I) (28 mg, 0.060 mmol, 1 equiv), prepared according toGrushin's protocol,⁶ and silver acetate (10 mg, 0.060 mmol, 1 equiv)were stirred in toluene (0.5 mL). After 1.5 h the mixture was filteredthrough a Celite plug and concentrated to 1 mL. PAd₃ (20 mg, 0.046 mmol,1 equiv) was then added to the solution and stirred for 10 min. Theresulting mixture was evaporated, redissolved in toluene (0.5 mL), anddiluted with ether (10 mL). After sonication, the resulting solid wascollected by filtration and aspirated for 0.5 h, yielding 23 mg (57%) ofthe metal complex as a yellow powder.

¹H NMR (501 MHz, CD₂Cl₂) δ 7.30 (d, J=7.9 Hz, 2H), 6.82 (t, J=7.3 Hz,2H), 6.77 (t, J=7.1 Hz, 1H), 2.42 (br, 18H), 1.86 (br, 9H), 1.79 (s,3H), 1.72-1.52 (m, 18H).

¹³C{¹H} NMR (126 MHz, CD₂Cl₂) δ 186.9, 141.0, 135.8 (d, J=3.0 Hz),126.9, 123.5, 49.1 (d, J=6.8 Hz), 42.3, 36.4, 29.4 (d, J=7.9 Hz), 23.6.

³¹P{¹H} NMR (203 MHz, CD₂Cl₂) δ 68.2.

HRMS (ESI) m/z calculated for Pd(PAd₃)(Ph)(MeCN) cation C₃₈H₅₃NPPd660.2950, found 660.2944.

Example 5—Preparation of SePAd₃

PAd₃ (11 mg, 25 μmol, 1 equiv) and selenium (9 mg, 95 μmol, 3.8 equiv)were dissolved in THF (2 mL) inside the glove box and stirred for 1 h.After removal of excess selenium by decantation, the mother liquor wasevaporated under vacuum to yield 13 mg (99%) of SePAd₃ as a whitepowder.

¹H NMR (501 MHz, CDCl₃) δ 2.41 (br, 18H), 1.97 (br, 9H), 1.79-1.33 (m,18H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 48.15 (d, J=19.6 Hz), 40.14 (br), 36.53(br), 29.17 (d, J=8.5 Hz).

³¹P{¹H} NMR (203 MHz, CDCl₃) δ 79.69 (s, ¹J_(P-Se)=669.9 Hz).

Examples 6-44: Suzuki-Miyaura Coupling and Characterization of Products

The following products were prepared via Suzuki-Miyaura with PAd₃ metalcatalyst. As described in the procedures below, the PAd₃ metal catalystwas generated in situ by addition of a THF stock solution ofbis-{2-[(acetyl-κO)amino]phenyl-κC}bis[μ-(p-toluenesulfonate)]dipalladium(3) and PAd₃ ligand. The catalyst formed in situ is described andcharacterized in Example 3 and illustrated in FIG. 13 .

To a mixture of 4-chloroanisole (62 μL, 0.50 mmol, 1 equiv),1-napthylboronic acid (94 mg, 0.55 mmol, 1.1 equiv), and K₃PO₄.H₂O (0.35g, 1.5 mmol, 3 equiv) was added toluene (800 μL), a THF stock solutionof 3 and PAd₃ (100 μL, 0.25 μmol Pd/PAd₃) and the mixture was stirred atroom temperature for 5 h. The reaction mixture was diluted with ethylacetate then extracted with water. The combined organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 104 mg of 6 (89%) was obtained as a white solid. NMRspectroscopic data agreed with literature values.

A mixture of 2-chlorobenzonitrile (69 mg, 0.50 mmol, 1 equiv),4-tolylboronic acid (75 mg, 0.55 mmol, 1.1 equiv), THF (100 μL) werestirred into slurry, added K₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2 equiv) thena THF stock solution of 3 and PAd₃ (10 μL, 0.025 μmol Pd/PAd₃). Thereaction vial was capped then taken outside the glove box to an oil bathpreset at 100° C. for 10 min. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 92 mg (95%) of 7 was obtained as a colorless crystallinesolid. NMR spectroscopic data agreed with literature values.

A mixture of 1-chloro-2-nitrobenzene (79 mg, 0.50 mmol, 1 equiv),4-chlorophenylboronic acid (80 mg, 0.51 mmol, 1.02 equiv), and THF (100μL) were stirred into slurry. Then K₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2equiv) was added followed by a THF stock solution of 3 and PAd₃ (10 μLin THF, 0.025 μmol of Pd/PAd₃). The reaction vial was capped then takenoutside the glove box to an oil bath preset at 100° C. for 10 min. Thereaction mixture was diluted with ethyl acetate then extracted withwater. The combined organic layers were evaporated and the crude productwas purified by flash chromatography. After drying, 114 mg (97%) of 8was obtained as a light yellow oil. NMR spectroscopic data agreed withliterature values.

A mixture of 2-chloropyridine (47 μL, 0.50 mmol, 1 equiv),(4-isobutoxyphenyl)boronic acid (107 mg, 0.55 mmol, 1.1 equiv), andn-butanol (200 μL) were stirred into slurry. Then K₃PO₄.5H₂O (0.33 g,1.1 mmol, 2.2 equiv) was added followed by a THF stock solution of 3 andPAd₃ (10 μL, 0.025 μmol of Pd/PAd₃). The reaction vial was capped thentaken outside the glove box to an oil bath preset at 100° C. for 1 h.The reaction mixture was diluted with ethyl acetate then extracted withwater. The combined organic layers were evaporated and the crude productwas purified by flash chromatography. After drying, 84 mg (74%) of 9 wasobtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 8.67 (ddd, J=4.9, 1.8, 1.0 Hz, 1H), 8.00-7.92(m, 2H), 7.77-7.66 (m, 2H), 7.19 (ddd, J=7.2, 4.9, 1.4 Hz, 1H),7.05-6.98 (m, 2H), 3.80 (d, J=6.5 Hz, 2H), 2.14 (dp, J=13.3, 6.7 Hz,1H), 1.07 (d, J=6.7 Hz, 6H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 160.2, 157.2, 149.5, 136.6, 131.8, 128.1,121.3, 119.8, 114.7, 74.5, 28.3, 19.3.

HRMS (ESI) m/z calculated for C₁₅H₁₇NO (M+1) 228.1383, found 228.1392.

A mixture of 2-chloro-4,6-dimethoxypyrimidine (87 mg, 0.50 mmol, 1equiv), 2-napthylboronic acid (95 mg, 0.55 mmol, 1.1 equiv), THF (150μL) were stirred into slurry. Then K₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2equiv) was added followed by a THF stock solution of 3 and PAd₃ (10 μL,0.025 μmol of Pd/PAd₃). The reaction vial was capped then taken outsidethe glove box to an oil bath preset at 100° C. for 5 h. The reactionmixture was diluted with ethyl acetate then extracted with water. Thecombine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 106 mg (80%) of 10 wasobtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 8.99-8.92 (m, 1H), 8.22 (ddt, J=7.0, 2.7, 1.4Hz, 1H), 7.97 (ddt, J=23.5, 8.1, 1.4 Hz, 2H), 7.64-7.51 (m, 3H),6.14-6.09 (m, 1H), 4.11-4.06 (m, 6H).

¹³C{¹H}{¹H} NMR (126 MHz, CDCl₃) δ 171.3, 165.7, 135.5, 134.2, 131.1,130.6, 129.4, 128.5, 126.5, 126.3, 125.7, 125.1, 88.0, 54.2.

HRMS (ESI) m/z calculated for C₁₆K₄N₂O₂ (M+1) 267.1128, found 267.1123.

To a mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (88 mg, 0.50 mmol,1 equiv), 2,6-difluorophenylboronic acid (118 mg, 0.75 mmol, 1.5 equiv),and K₂CO₃.1.5H₂O (0.25 g, 1.5 mmol, 3 equiv) was added THF (300 μL) thena THF stock solution of 3 and PAd₃ (200 μL in THF, 0.5 μmol) and themixture was stirred at room temperature for 5 h. The reaction mixturewas diluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 118 mg (93%) of 11 was obtained as awhite solid.

¹H NMR (501 MHz, CDCl₃) δ 7.39 (tt, J=8.4, 6.2 Hz, 1H), 7.02-6.93 (m,2H), 4.07 (s, 6H).

¹³C{¹H}{¹H} NMR (126 MHz, CDCl₃) δ 172.5, 170.6 (t, J=1.6 Hz), 160.6(dd, J=255.1, 6.0 Hz), 131.9 (t, J=11.3 Hz), 115.4 (t, J=16.4 Hz), 111.9(dd, J=20.2, 5.0 Hz), 55.5.

HRMS (ESI) m/z calculated for C₁₁H₉F₂N₃O₂ (M+1) 254.0736, found254.0722.

To a mixture of2,4-di-tert-butyl-6-(5-chloro-2H-benzotriazol-2-yl)phenol (179 mg, 0.50mmol, 1 equiv), 4-trifluoromethylphenylboronic acid (114 mg, 0.60 mmol,1.2 equiv), K₃PO₄.5H₂O (0.36 g, 1.2 mmol, 2.4 equiv), and KO^(t)Bu (56mg, 0.50 mmol, 1 equiv) was added a THF stock solution of 3 and PAd₃ (2mL in THF, 5 μmol of Pd/PAd₃). The mixture was stirred at 70° C. for 5h. The reaction mixture was diluted with ethyl acetate then extractedwith water. The combine organic layers were evaporated and the crudeproduct was purified by flash chromatography. After drying, 224 mg (96%)of 12 was obtained as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 11.63 (s, 1H), 8.22 (d, J=2.4 Hz, 1H), 8.01(t, J=1.2 Hz, 1H), 7.91 (dd, J=8.9, 0.9 Hz, 1H), 7.71-7.58 (m, 5H), 7.37(d, J=2.4 Hz, 1H), 1.44 (s, 9H), 1.32 (s, 9H).

¹³C{¹H}{¹H} NMR (126 MHz, CDCl₃) δ 145.7, 143.0, 142.0, 141.3, 140.7,138.1, 137.6, 128.8 (q, J=32.6 Hz), 126.7, 126.7, 125.0 (q, J=3.7 Hz),124.4, 124.1, 123.1 (q, J=272.2 Hz), 117.1, 115.1, 114.6, 34.7, 33.6,30.5, 28.5.

HRMS (ESI) m/z calculated for C₂₇H₂₈F₃N₃O (M+1) 468.2257, found468.2257.

To a mixture of haloperidol (94 mg, 0.25 mmol, 1 equiv),furan-3-ylboronic acid (42 mg, 0.38 mmol, 1.5 equiv),1,3,5-trimethyoxybenzene (42 mg, 0.25 mmol, 1 equiv) as internalstandard, and K₃PO₄.H₂O (0.17 g, 0.75 mmol, 3 equiv) was added THF (400μL) and a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol ofPd/PAd₃) and the mixture was stirred at 100° C. for 12 h. The NMR yieldof 13 was 80% determined against the internal standard. The reactionmixture was diluted with ethyl acetate then extracted with water. Thecombine organic layers were evaporated and the crude product waspurified by flash chromatography and preparative HPLC. After drying, 56mg (55%) of 13 was obtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 8.09-8.01 (m, 2H), 7.75 (t, J=1.2 Hz, 1H),7.49 (d, J=3.5 Hz, 5H), 7.21-7.12 (m, 2H), 6.72 (dd, J=1.8, 0.9 Hz, 1H),3.02 (t, J=7.1 Hz, 2H), 2.83 (d, J=11.2 Hz, 2H), 2.56-2.44 (m, 4H), 2.04(td, J=16.6, 14.3, 9.7 Hz, 4H), 1.79-1.72 (m, 2H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 198.4, 165.6 (d, J=254.3 Hz), 143.7,138.5, 131.2, 130.7, 130.7, 126.0, 125.8, 125.0, 115.7, 115.5, 108.8,71.3, 57.9, 49.4, 38.4, 36.3, 22.0.

HRMS (ESI) m/z calculated for C₂₅H₂₇FNO₃ (M+1) 408.1969, found 408.1960.

To a mixture of montelukast sodium salt (152 mg, 0.25 mmol, 1 equiv),3,4,5-trifluorophenyl boronic acid (53 mg, 0.30 mmol, 1.2 equiv), andK₃PO₄.5H₂O (0.18 g, 0.60 mmol, 2.4 equiv) was added THF (2 mL) then aTHF stock solution of 3 and PAd₃ (1 mL, 2.5 μmol of Pd/PAd₃). Themixture was stirred at 100° C. for 5 h. The reaction mixture was dilutedwith ethyl acetate then extracted with saturated ammonium chloride thenwater. The combine organic layers were evaporated and the crude productwas purified by flash chromatography. After drying, 152 mg (89%) of 14was obtained as yellow solid.

¹H NMR (500 MHz, CDCl₃) δ 8.18 (d, J=1.8 Hz, 1H), 8.10 (d, J=8.5 Hz,1H), 7.82 (d, J=8.4 Hz, 1H), 7.74 (d, J=1.9 Hz, 1H), 7.67 (d, J=8.6 Hz,1H), 7.62 (dd, J=5.0, 1.8 Hz, 1H), 7.59 (d, J=17.1 Hz, 1H), 7.48 (d,J=17.1 Hz, 1H), 7.40 (m, 1H), 7.37-7.28 (m, 5H), 7.18-7.13 (m, 2H), 7.10(ddd, J=7.6, 5.8, 3.0 Hz, 1H), 5.29 (s, 1H), 4.01 (t, J=7.2 Hz, 1H),3.17 (ddd, J=13.5, 11.2, 5.1 Hz, 1H), 2.90 (ddd, J=13.5, 11.2, 5.4 Hz,1H), 2.65 (d, J=13.1 Hz, 1H), 2.57 (d, J=16.2 Hz, 1H), 2.45 (d, J=13.1Hz, 1H), 2.38 (d, J=16.1 Hz, 1H), 2.28-2.09 (m, 2H), 1.60 (d, J=4.9 Hz,6H), 0.71-0.24 (m, 4H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 176.3, 156.9, 151.5 (ddd, J=249.9, 10.0,4.2 Hz), 147.7, 145.2, 143.6, 140.2, 139.7 (dt, J=253.3, 15.4 Hz),139.4, 136.5, 136.4, 136.3 (m), 135.4, 131.5, 129.0, 128.6, 128.5,128.4, 127.1, 126.9, 126.5, 126.5, 126.4, 125.6, 125.4, 125.0, 119.4,111.4 (dd, J=12.6, 5.0 Hz), 73.8, 50.3, 40.3, 40.0, 38.9, 32.3, 31.8,16.8, 12.7, 12.4.

HRMS (ESI) m/z calculated for C₄₁H₃₈F₃NO₃S (M+1) 682.2597, found682.2598.

To a mixture of fenofibrate (90 mg, 0.25 mmol, 1 equiv),cyclopropylboronic acid (32 mg, 0.38 mmol, 1.5 equiv), and K₃PO₄.H₂O(0.18 g, 0.75 mmol, 3 equiv) was added toluene (400 μL) then a THF stocksolution of 3 and PAd₃ (50 μL, 0.125 μmol of Pd/PAd₃). The mixture wasstirred at 100° C. for 5 h. The reaction mixture was diluted with ethylacetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 84 mg (92%) of 15 was obtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 7.80-7.72 (m, 2H), 7.72-7.66 (m, 2H),7.19-7.12 (m, 2H), 6.91-6.84 (m, 2H), 5.11 (hept, J=6.3 Hz, 1H), 1.99(tt, J=8.4, 5.0 Hz, 1H), 1.68 (s, 6H), 1.23 (d, J=6.3 Hz, 6H), 1.13-1.05(m, 2H), 0.85-0.78 (m, 2H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 195.2, 173.2, 159.3, 149.2, 135.2, 131.9,131.0, 130.1, 125.2, 117.1, 79.3, 69.3, 25.4, 21.5, 15.7, 10.3.

HRMS (ESI) m/z calculated for C₂₃H₂₆O₄ (M+1) 367.1904, found 367.1888.

To a mixture of glibenclamide (247 mg, 0.50 mmol, 1 equiv),N-Boc-pyrroleboronic acid (127 mg, 0.60 mmol, 1.2 equiv),1,3,5-trimethyoxybenzene (84 mg, 0.50 mmol, 1 equiv) as internalstandard, and K₃PO₄.5H₂O (0.36 g, 1.2 mmol, 2.4 equiv) was added a THFstock solution of 3 and PAd₃ (2 mL in THF, 5 μmol of Pd/PAd₃). Themixture was stirred at 100° C. for 5 h. The crude NMR yield was 65%versus the internal standard. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatographyand preparative HPLC. After drying, 116 mg (37%) of 16 was obtained as awhite solid.

¹H NMR (501 MHz, CDCl₃) δ 8.13 (d, J=2.4 Hz, 1H), 7.83 (t, J=5.8 Hz,1H), 7.78 (d, J=8.3 Hz, 2H), 7.43-7.31 (m, 3H), 7.26 (dd, J=3.3, 1.8 Hz,1H), 6.86 (d, J=8.5 Hz, 1H), 6.37 (d, J=7.9 Hz, 1H), 6.14 (t, J=3.3 Hz,1H), 6.11 (dd, J=3.3, 1.8 Hz, 1H), 3.75 (s, 3H), 3.69 (q, J=6.6 Hz, 2H),3.56-3.47 (m, 1H), 2.96 (t, J=6.9 Hz, 2H), 1.80-1.72 (m, 2H), 1.64-1.46(m, 4H), 1.34 (s, 9H), 1.30-1.03 (m, 4H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 165.2, 156.6, 150.1, 149.2, 146.3, 137.7,133.8, 133.6, 133.0, 129.9, 127.7, 127.2, 122.6, 120.3, 114.7, 110.6,110.6, 83.7, 56.0, 49.2, 40.5, 35.7, 33.0, 27.8, 25.4, 24.6.

HRMS (ESI) m/z calculated for C₃₂H₄₀N₄O₇S (M+1) 625.2691, found625.2700.

To a mixture of 5-R-rivaroxaban (55 mg, 0.13 mmol, 1 equiv),3,5-bis(trifluoromethyl) phenylboronic acid (35 mg, 0.14 mmol, 1.1equiv), 1,3,5-trimethyoxybenzene (21 mg, 0.13 mmol, 1 equiv) as internalstandard, and K₃PO₄.5H₂O (82 mg, 0.28 mmol, 2.2 equiv) was added a THFstock solution of 3 and PAd₃ (2.5 mL, 6.25 μmol of Pd/PAd₃). The mixturewas stirred at 100° C. for 5 h. The crude NMR yield was 83% versus theinternal standard. The reaction mixture was diluted with ethyl acetatethen extracted with water. The combine organic layers were evaporatedand the crude product was purified by flash chromatography andpreparative HPLC. After drying, 43 mg (56%) of 17 was obtained as awhite solid.

¹H NMR (501 MHz, CDCl₃) δ 7.94 (s, 2H), 7.76 (s, 1H), 7.55-7.45 (m, 3H),7.33 (d, J=3.9 Hz, 1H), 7.30-7.23 (m, 2H), 6.90 (s, 1H), 4.82 (dd,J=6.0, 3.0 Hz, 1H), 4.26 (s, 2H), 4.04 (t, J=8.9 Hz, 1H), 3.99-3.93 (m,2H), 3.88-3.77 (m, 2H), 3.76-3.63 (m, 3H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 166.9, 162.1, 154.4, 145.6, 139.0, 137.4,136.6, 135.5, 132.3 (q, J=34.0 Hz), 127.6 (q, J=476.3 Hz), 126.3, 126.0,124.1, 121.9, 119.2, 71.9, 68.6, 64.1, 49.7, 47.7, 42.4.

HRMS (ESI) m/z calculated for C₂₇H₂₁F₆N₃O₅S (M+1) 614.1179, found614.1196.

To a mixture of 4-chloroanisole (62 μL, 0.50 mmol, 1 equiv),phenylboronic acid (67 mg, 0.55 mmol, 1.1 equiv), and K₃PO₄.H₂O (0.35 g,1.5 mmol, 3 equiv) was added toluene (800 μL) then a THF stock solutionof 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixture was stirred atroom temperature for 5 h. The reaction mixture was diluted with ethylacetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 75 mg (81%) of 18 was obtained as a white solid. NMRspectroscopic data agreed with literature values.

To a mixture of 4-chloroanisole (62 μL, 0.50 mmol, 1 equiv),3,5-bis(trifluoromethyl) phenylboronic acid (142 mg, 0.55 mmol, 1.1equiv), and K₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2 equiv) was added THF (400μL) then a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol ofPd/PAd₃). The mixture was stirred at room temperature for 5 h. Thereaction mixture was diluted with ethyl acetate then extracted withwater. The combine organic layers were evaporated and the crude productwas purified by flash chromatography. After drying, 146 mg (91%) of 19was obtained as a colorless oil. NMR spectroscopic data agreed withliterature values.

To a mixture of 2-chloro-1,3-dimethylbenzene (66 μL, 0.50 mmol, 1equiv), 1-napthylboronic acid (129 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at 100° C. for 5 h. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 93 mg (80%) of 20 was obtained as a white solid. NMRspectroscopic data agreed with literature values.

To a mixture of 2-chlorotoluene (59 μL, 0.50 mmol, 1 equiv),2,6-dimethoxyphenylboronic acid (136 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.H₂O (0.35 g, 1.5 mmol, 3 equiv) was added toluene (400 μL) then acatalyst stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃).The mixture was stirred at 50° C. for 5 h. The reaction mixture wasdiluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 79 mg (70%) of 21 was obtained as awhite solid. NMR spectroscopic data agreed with literature values.

To a mixture of 2-chlorotoluene (59 μL, 0.50 mmol, 1 equiv),2,6-dimethylphenylboronic acid (112 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at 100° C. for 9 h. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 69 mg (70%) of 22 was obtained as a colorless oil. NMRspectroscopic data agreed with literature values.

To a mixture of 1-bromo-2,4-dimethoxybenzene (72 μL, 0.50 mmol, 1equiv), cyclopropylboronic acid (64 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.H₂O (0.35 mg, 1.5 mmol, 3 equiv) was added toluene (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃) and themixture was stirred at 100° C. for 5 h. The reaction mixture was dilutedwith ethyl acetate then extracted with water. The combine organic layerswere evaporated and the crude product was purified by flashchromatography. After drying, 80 mg (90%) of 23 was obtained as acolorless oil. NMR spectroscopic data agreed with literature values.

To a mixture of 3-chloropyridine (48 μL, 0.50 mmol, 1 equiv),1-napthylboronic acid (95 mg, 0.55 mmol, 1.1 equiv), and K₃PO₄.H₂O (0.35g, 1.5 mmol, 3 equiv) was added toluene (400 μL) then a THF stocksolution of 3 and PAd₃ (100 μL, 0.25 μmol). The mixture was stirred at90° C. for 5 h. The reaction mixture was diluted with ethyl acetate thenextracted with water. The combine organic layers were evaporated and thecrude product was purified by flash chromatography. After drying, 70 mg(68%) of 24 was obtained as a white solid. NMR spectroscopic data agreedwith literature values.

To a mixture of 3-chloropyridine (48 μL, 0.50 mmol, 1 equiv),4-tolylboronic acid (75 mg, 0.55 mmol, 1.1 equiv), and K₃PO₄.H₂O (0.35g, 1.5 mmol, 3 equiv) was added toluene (400 μL) then a THF stocksolution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixture wasstirred at 90° C. for 5 h. The reaction mixture was diluted with ethylacetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 53 mg (63%) of 25 was obtained as a white solid. NMRspectroscopic data agreed with literature values.

To a mixture of 3-chloropyridine (48 μL, 0.50 mmol, 1 equiv),3,5-bis(trifluoromethyl) phenylboronic acid (142 mg, 0.55 mmol, 1.1equiv), and K₃PO₄.H₂O (0.35 mg, 1.5 mmol, 3 equiv) was added toluene(400 μL) then a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol ofPd/PAd₃). The mixture was stirred at 90° C. for 5 h. The reactionmixture was diluted with ethyl acetate then extracted with water. Thecombine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 143 mg (98%) of 26 wasobtained as a white solid. NMR spectroscopic data agreed with literaturevalues.

To a mixture of 3-chloropyridine (48 μL, 0.50 mmol, 1 equiv),(4-isobutoxyphenyl)boronic acid (107 mg, 0.55 mmol, 1.1 equiv), andK₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at 100° C. for 12 h. The reaction mixture wasdiluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 96 mg (84%) of 27 was obtained as acolorless oil.

¹H NMR (501 MHz, CDCl₃) δ 8.85-8.80 (m, 1H), 8.57-8.51 (m, 1H), 7.80(dt, J=8.2, 1.9 Hz, 1H), 7.53-7.46 (m, 2H), 7.31 (dd, J=7.9, 5 Hz, 1H),7.04-6.97 (m, 2H), 3.76 (d, J=6.6 Hz, 2H), 2.11 (dq, J=13.3, 6.7 Hz,1H), 1.05 (d, J=6.9 Hz, 6H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 159.5, 148.0, 147.8, 136.3, 133.8, 129.9,128.1, 123.5, 115.1, 74.5, 28.3, 19.3.

HRMS (ESI) m/z calculated for C₁₅H₁₇NO (M+1) 228.1383, found 228.1377.

To a mixture of 2,6-dichloropyrazine (37 mg, 0.25 mmol, 1 equiv),3,5-bis(trifluoromethyl)phenylboronic acid (142 mg, 0.55 mmol, 2.2equiv), and K₃PO₄.5H₂O (0.33 g, 1.1 mmol, 4.4 equiv) was added THF (400μL) then a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol ofPd/PAd₃). The mixture was stirred at 70° C. for 5 h. The reactionmixture was diluted with ethyl acetate then extracted with water. Thecombine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 110 mg (87%) of 28 wasobtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 9.20 (s, 2H), 8.62-8.58 (m, 4H), 8.07 (s, 2H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 149.2, 141.5, 137.9, 132.8 (q, J=33.7Hz), 127.1, 123.9, 123.1 (q, J=273.4 Hz).

HRMS (ESI) m/z calculated for C₂₀H₈F₁₂N₂ (M+1) 505.0569, found 505.0563.

To a mixture of 2-chlorotoluene (59 μL, 0.50 mmol, 1 equiv),N-Boc-2-pyrroleboronic acid (158 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at room temperature for 5 h. The reaction mixture wasdiluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 124 mg (96%) of 29 was obtained as acolorless oil. NMR spectroscopic data agreed with literature values.

To a mixture of 2-chloro-3-methylquinoxaline (89 mg, 0.50 mmol, 1equiv), N-Boc-2-pyrroleboronic acid (158 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at 70° C. for 5 h. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 148 mg (96%) of 30 was obtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 8.09-7.98 (m, 2H), 7.74-7.63 (m, 2H), 7.43(dd, J=3.4, 1.7 Hz, 1H), 6.44 (dd, J=3.3, 1.7 Hz, 1H), 6.33 (t, J=3.4Hz, 1H), 2.56 (s, 3H), 1.17 (s, 9H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 154.5, 149.6, 148.6, 141.2, 140.3, 130.7,129.8, 129.1, 129.0, 128.3, 122.5, 115.6, 111.4, 84.2, 27.4, 23.0.

HRMS (ESI) m/z calculated for C₁₈H₁₉N₃O₂ (M+1) 310.1550, found 310.1552.

To a mixture of 2-chloropyrazine (44 μL, 0.50 mmol, 1 equiv),3,4,5-trifluorophenyl-boronic acid (132 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at 70° C. for 5 h. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 77 mg (73%) of 31 was obtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 8.98 (d, J=1.6 Hz, 1H), 8.66-8.62 (m, 1H),8.57 (d, J=2.5 Hz, 1H), 7.75-7.65 (m, 2H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 151.7 (ddd, J=250.7, 10.2, 4.0 Hz), 149.4(dt, J=1.3, 2.5 Hz), 144.3, 144.0, 141.6, 140.9 (dt, J=255.8, 15.4 Hz),132.3 (dt, J=5.0, 7.6 Hz), 111.0 (dd, J=17.1, 5.5 Hz).

HRMS (ESI) m/z calculated for C₁₀H₅F₃N₂ (M+1) 211.0478, found 211.0471.

To a mixture of 2-chloropyrazine (44 μL, 0.50 mmol, 1 equiv),(6-methoxypyridin-3-yl)boronic acid (115 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3.0 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at 70° C. for 5 h. The reaction mixture was dilutedwith ethyl acetate then extracted with water. The combine organic layerswere evaporated and the crude product was purified by flashchromatography. After drying, 77 mg (82%) of 32 was obtained as a whitesolid.

¹H NMR (501 MHz, CDCl₃) δ 8.89 (d, J=1.6 Hz, 1H), 8.72 (d, J=2.6 Hz,1H), 8.54-8.49 (m, 1H), 8.41 (d, J=2.6 Hz, 1H), 8.15 (dd, J=8.7, 2.5 Hz,1H), 6.79 (d, J=8.7 Hz, 1H), 3.92 (s, 3H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 165.2, 150.6, 145.7, 144.2, 142.8, 141.3,137.1, 125.6, 111.4, 53.8.

HRMS (ESI) m/z calculated for C₁₀H₉N₃O (M+1) 118.0818, found 118.0814.

To a mixture of 2-chloro-4,6-dimethoxypyrimidine (87 mg, 0.50 mmol, 1equiv), N-Boc-2-pyrroleboronic acid (116 mg, 0.55 mmol, 1.1 equiv), andK₃PO₄.5H₂O (0.33 g, 1.1 mmol, 2.2 equiv) was added n-butanol (400 μL)then a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃).The mixture was stirred at room temperature for 5 h. The reactionmixture was diluted with ethyl acetate then extracted with water. Thecombine organic layers were evaporated and the crude product waspurified by flash chromatography. After drying, 147 mg (96%) of 33 wasobtained as a colorless oil.

¹H NMR (501 MHz, CDCl₃) δ 7.33 (dd, J=3.1, 1.7 Hz, 1H), 6.77 (dd, J=3.4,1.7 Hz, 1H), 6.26 (t, J=3.3 Hz, 1H), 5.95 (s, 1H), 3.97 (s, 6H), 1.48(s, 9H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 171.0, 159.4, 149.0, 133.0, 124.8, 117.9,110.5, 87.6, 83.6, 54.0, 27.7.

HRMS (ESI) m/z calculated for C₁₅H₁₉N₃O₄ (M+1) 306.1448, found 306.1431.

To a mixture of 2-chlorobenzonitrile (69 mg, 0.50 mmol, 1 equiv),(3,5-dimethylisoxazol-4-yl)boronic acid (106 mg, 0.75 mmol, 1.5 equiv),and K₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at 100° C. for 9 h. The reaction mixture was dilutedwith ethyl acetate then extracted with water. The combine organic layerswere evaporated and the crude product was purified by flashchromatography. After drying, 78 mg (79%) of 34 was obtained as acolorless oil. NMR spectroscopic data agreed with literature values.

To a mixture of 2-chloropyridine (47 μL, 0.50 mmol, 1 equiv),furan-3-ylboronic acid (84 mg, 0.75 mmol, 1.5 equiv), and K₃PO₄.H₂O(0.35 g, 1.5 mmol, 3 equiv) was added THF (400 μL) then a THF stocksolution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixture wasstirred at 100° C. for 12 h. The reaction mixture was diluted with ethylacetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 80 mg (92%) of 35 was obtained as a colorless oil. NMRspectroscopic data agreed with literature values.

To a mixture of 2-chloropyridine (47 μL, 0.50 mmol, 1 equiv),quinolin-3-ylboronic acid (130 mg, 0.75 mmol, 1.5 equiv), and K₃PO₄.H₂O(0.35 g, 1.5 mmol, 3 equiv) was added n-butanol (400 μL) then a THFstock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixturewas stirred at 100° C. for 5 h. The reaction mixture was diluted withethyl acetate then extracted with water. The combine organic layers wereevaporated and the crude product was purified by flash chromatography.After drying, 83 mg (80%) of 36 was obtained as a white solid. NMRspectroscopic data agreed with literature values.

To a mixture of 2-chloropyridine (47 μL, 0.50 mmol, 1 equiv),2,4-difluorophenylboronic acid (118 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at 70° C. for 4 h. The reaction mixture was dilutedwith ethyl acetate then extracted with water. The combine organic layerswere evaporated and the crude product was purified by flashchromatography. After drying, 89 mg (93%) of 37 was obtained as acolorless oil. NMR spectroscopic data agreed with literature values.

To a mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (88 mg, 0.50 mmol,1 equiv), furan-2-ylboronic acid (84 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at room temperature for 1.5 h. The reaction mixturewas diluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 93 mg (90%) of 38 was obtained as awhite solid.

¹H NMR (501 MHz, CDCl₃) δ 7.64-7.59 (m, 1H), 7.44 (d, J=3.5 Hz, 1H),6.53 (dd, J=3.4, 1.7 Hz, 1H), 4.03 (s, 6H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 172.6, 166.5, 150.1, 146.6, 117.4, 112.5,55.2. HRMS (ESI) m/z calculated for C₉H₉N₃O₃ (M+1) 208.0717, found208.0706.

To a mixture of 2-chloro-4,6-dimethoxy-1,3,5-triazine (88 mg, 0.50 mmol,1 equiv), thiophen-2-ylboronic acid (96 mg, 0.75 mmol, 1.5 equiv), andK₃PO₄.5H₂O (0.45 mg, 1.5 mmol, 3 equiv) was added THF (400 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at room temperature for 5 h. The reaction mixturewas diluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 104 mg (93%) of 39 was obtained as awhite solid. NMR spectroscopic data agreed with literature values.

To a mixture of 4,7-dibromobenzo[c][1,2,5]thiadiazole (147 mg, 0.50mmol, 1 equiv), thiophen-2-ylboronic acid (192 mg, 1.50 mmol, 3 equiv),and K₃PO₄.5H₂O (0.90 g, 3.0 mmol, 6 equiv) was added THF (900 μL) then aTHF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). Themixture was stirred at room temperature for 1 h. The reaction mixturewas diluted with ethyl acetate then extracted with water. The combineorganic layers were evaporated and the crude product was purified byflash chromatography. After drying, 143 mg (95%) of 40 was obtained asan orange solid. NMR spectroscopic data agreed with literature values.

To a mixture of 2-chloro-1,3-dimethylbenzene (66 μL, 0.50 mmol, 1equiv), methylboronic acid (45 mg, 0.75 mmol, 1.5 equiv),1,3,5-trimethyoxybenzene (84 mg, 0.50 mmol, 1 equiv) as internalstandard, and K₃PO₄.5H₂O (0.45 g, 1.5 mmol, 3 equiv) was added THF (400μL) then a THF stock solution of 3 and PAd₃ (100 μL, 0.25 μmol ofPd/PAd₃). The mixture was stirred at 50° C. for 5 h. The crude NMR yieldwas 90% versus the internal standard. The reaction mixture was dilutedwith ethyl acetate then extracted with water. The combine organic layerswere evaporated and the crude product was purified by flashchromatography. After drying, 30 mg (50%) of 41 was obtained as acolorless oil.

To a mixture of fenofibrate (90 mg, 0.25 mmol, 1 equiv), methylboronicacid (30 mg, 0.50 mmol, 2 equiv), 1,3,5-trimethyoxybenzene (42 mg, 0.25mmol, 1 equiv) as internal standard, and K₃PO₄.H₂O (0.18 g, 0.75 mmol, 3equiv) was added toluene (400 μL) then a THF stock solution of 3 andPAd₃ (50 μL, 0.125 μmol of Pd/PAd₃). The mixture was stirred at 100° C.for 5 h. The crude NMR yield was 88% versus internal standard. Thereaction mixture was diluted with ethyl acetate then extracted withwater. The combine organic layers were evaporated and the crude productwas purified by flash chromatography and preparative HPLC. After drying,65 mg (76%) of 42 was obtained as a white solid.

¹H NMR (501 MHz, CDCl₃) δ 7.80-7.73 (m, 2H), 7.71-7.65 (m, 2H), 7.28 (d,J=7.9 Hz, 2H), 6.92-6.84 (m, 2H), 5.10 (hept, J=6.3 Hz, 1H), 2.44 (s,3H), 1.67 (s, 6H), 1.22 (d, J=6.3 Hz, 6H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 195.3, 173.2, 159.3, 142.7, 135.4, 131.9,130.9, 130.0, 128.9, 117.1, 79.3, 69.3, 25.4, 21.6, 21.5.

HRMS (ESI) m/z calculated for C₂₁H₂₄O₄ (M+1) 341.1747, found 341.1749.

To a mixture of 4,7-bis(5-bromothiophen-2-yl)benzo[c][1,2,5]thiadiazole(115 mg, 0.25 mmol, 1 equiv),²⁹ (9,9-dimethyl-9H-fluoren-2-yl)boronicacid (131 mg, 0.55 mmol, 2.2 equiv), and K₃PO₄.5H₂O (0.33 g, 1.1 mmol,4.4 equiv) was added THF (900 μL) then a THF stock solution of 3 andPAd₃ (100 μL, 0.25 μmol of Pd/PAd₃). The mixture was stirred at roomtemperature for 1 h. The reaction mixture was diluted with ethyl acetatethen extracted with water. The combine organic layers were evaporatedand the crude product was purified by flash chromatography. Afterdrying, 152 mg (89%) of 43 was obtained as a dark red solid.

¹H NMR (501 MHz, CDCl₃) δ 8.19 (d, J=3.9 Hz, 2H), 7.97 (s, 2H),7.82-7.72 (m, 8H), 7.54-7.46 (m, 4H), 7.38 (pd, J=7.4, 1.5 Hz, 4H), 1.59(s, 12H).

¹³C{¹H} NMR (126 MHz, CDCl₃) δ 154.4, 153.9, 152.7, 146.3, 139.2, 138.7,138.4, 133.2, 128.6, 127.5, 127.1, 125.8, 125.3, 125.0, 124.0, 122.7,120.5, 120.1, 120.1, 47.0, 27.2.

HRMS (ESI) m/z calculated for C₄₄H₃₃N₂S₃ (M+1) 685.1800, found 685.1782.

To a mixture of 4-chloroanisole (62 μL, 0.50 mmol, 1 equiv),isopropylboronic acid (66 mg, 0.75 mmol, 1.5 equiv), and K₃PO₄.H₂O (0.35mg, 1.5 mmol, 3 equiv) was added a toluene stock solution of 3 and PAd₃(2 mL, 5 μmol of Pd/PAd₃). The mixture was stirred at 100° C. for 5 h.The reaction mixture was diluted with ethyl acetate then extracted withwater. The combine organic layers were evaporated and the crude productwas purified by flash chromatography. After drying, 53 mg (70%) of 44was obtained as a colorless oil. NMR spectroscopic data agreed withliterature values.

Various embodiments of the invention have been described in fulfillmentof the various objectives of the invention. It should be recognized thatthese embodiments are merely illustrative of the principles of thepresent invention. Numerous modifications and adaptations thereof willbe readily apparent to those skilled in the art without departing fromthe spirit and scope of the invention.

The invention claimed is:
 1. A method of synthesizing atri-(adamantyl)phosphine compound, PAd₃, comprising: providing areaction mixture including di-(adamantyl)phosphine (PAd₂) and asubstituted adamantyl moiety of the formula R—X, and reacting the PAd₂and substituted adamantyl moiety via an S_(N)1 pathway to provide thePAd₃, wherein R is an adamantyl moiety selected from the groupconsisting of adamantyl, diamantyl, and triamantyl, and X is a leavinggroup operable for dissociation into an anion under the S_(N)1 pathway.2. The method of claim 1, wherein adamantyl moieties (Ad) of the PAd₃are independently selected from the group consisting of adamantane,diamantane, triamantane and derivatives thereof.
 3. The method of claim1, wherein the leaving group is selected from group consisting ofacetate, triflate, and hydroxyl.
 4. The method of claim 3, wherein theleaving group is acetate, and R is adamantyl.
 5. The method of claim 1,wherein yield of the PAd₃ is greater than 50 percent.
 6. The method ofclaim 1, wherein yield of the PAd₃ is greater than 60 percent.
 7. Themethod of claim 1, wherein synthesizing the tri-(adamantyl)phosphine isperformed at room temperature.
 8. The method of claim 1, wherein thedi-(adamantyl)phosphine (PAd₂) is di-1-adamantyl phosphine, and thesubstituted adamantyl moiety is 1-adamantylacetate.
 9. The method ofclaim 8, wherein the reaction mixture further comprises Me₃SiOTf.